Adrenoleukodystrophy (X-linked adenoleukodystrophy or X-ALD) is a rare, inherited disorder that leads to progressive damage to the brain, adrenal gland, peripheral nervous system, and eventually death. ALD belongs to the group of generic disorders called leukodystrophies, whose main feature is damage to myelin.
X-ALD presents three main phenotypes: (i) an adult adrenomyeloneuropathy (AMN) with axonopathy in spinal cords, (ii) cerebral adrenomyeloneuropathy with brain demyelination (cAMN), and (iii) childhood variant (cALD) characterized by severe cerebral demyelination.
X-ALD is the most frequently inherited leukodystrophy, with a minimum incidence of 1 in 17,000 males. The gene mutated in the disease (ABCD1) encodes for the ABCD1 protein, an ATP binding cassette transporter and an integral peroxisomal membrane protein involved in the import of very long-chain fatty acids (VLCFA, C≧22:0) and VLCFA-CoA esters into the peroxisome for degradation [Hetterm E. H. et al., Embo J. 1996, 15, 3813-3822; and van Roermund C. W. et al., Faseb J. 2008, 22, 4201-4208]. The defective function of the ABCD1 transporter leads to VLCFA accumulation in most organs and plasma.
Approximately 70% of male X-ALD patients develop primary adrenocortical insufficiency. In affected patients, adrenal hormone replacement therapy is mandatory and effective. However, this therapy does not influence the development or progression of neurological symptoms.
Some dietary treatments, for example, Lorenzo's oil (a 4:1 mixture of glyceryl trioleate and glyceryl trierucate) in combination with a diet low in VLCSFA (very long chain saturated fatty acids), have been used with limited success in the treatment of X-ALD.
To date, therapies targeting the immune system (immunosuppressive and/or immunomodulating) have not proven to be successful.
Lovastatin, an anti-cholesterol drug, appears to have some effect in vitro, but not in mice with the animal model of adrenoleukodystrophy [Yamada T. et al., J. Inherit. Metab. Dis. 2000, 23, 607-614].
Another therapeutic strategy is based on the use of histone deacetylase (HDAC) inhibitors 4-phenylbutyrate (4-PBA) and valproic acid (VPA). The poor response of 4-PBA was suggested to be caused by its short half-life and its capacity of inducing tachyphylaxis. The use of VPA for the treatment and/or prevention of X-ALD is described in ES 2303441 B1. However, its efficacy in improving the clinical symptoms of human patients has not been tested. Further, in a recent study in X-ALD patients, adverse effects such as trembling have been detected, which worsen the symptoms of the disease.
Currently, c-ALD can be treated by bone marrow transplant (BMT) from an allogeneic donor, or by infusion of genetically modified bone marrow cells that, within the brain, abrogate the aggressive microglia-based inflammatory reaction to the excess of VLCFA [Cartier N. et al., Science 2009, 326, 818-823]. However, BMT carries an elevated risk of mortality and morbidity, and the gene therapy approach is still at the early experimental stages. Both treatments can only be applied at the very first signs of disease, which means that most cALD patients do not have a valid therapeutic option.
There is no cure yet for AMN, although a clinical trial is ongoing to test the effect of an antioxidant treatment (NCT01495260). The chosen protocol is based on a wealth of studies in patients as well as in the mouse models of the disease that, taken together, extensively document that a complex interplay of oxidative stress and bioenergetic failure underlies the damaging effects of VLCFA [Lopez-Erauskin J. et al., Ann. Neurol. 2011, 70, 84-92; Fourcade S. et al., Hum. Mol. Genet. 2008, 17, 1762-1773; and Galino J. et al., Antioxid. Redox Signal 2011, 15, 2095-2107]. Recently, the use of a combination of N-acetylctysteine (NAC) and alpha lipoic acid (LA) has been disclosed as antioxidant therapy for the treatment and/or prevention of X-ALD in patent application WO 2011/144777 A1.
In view of the above, there is a need for new therapies for the treatment and/or prevention of X-ALD that overcome the previously mentioned drawbacks of the state of the art.
Pioglitazone is a drug of the class of thiazolidinediones or glitazones that shows hypoglycemic action. This compound is marketed under the tradename Actos® (Takeda Pharmaceuticals) as the monohydrochloride salt of the racemic mixture, for use in the treatment of diabetes mellitus type 2. Pharmacological studies indicate that Actos® improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis, and improves glycemic control while reducing circulating insulin levels. Pioglitazone is a chiral compound whose two enantiomers interconvert in vivo. Further no differences were found in the pharmacologic activity between the two enantiomers. Pioglitazone is a potent agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism. Pioglitazone was disclosed for the first time in the patent family corresponding to EP 0 193 256 A1 as a therapeutic agent for diabetes and hyperlipemia.
The inventors have surprisingly found that pioglitazone can be used in the treatment and/or prevention of X-ALD.